The world's first claudin18.2/PD-L1 double-specific antibody preclinical data release.

As shown in Figure 1, Claudin 18 (CLDN18) is a protein encoded by the CLDN 18 gene that belongs to the tight lying protein family of cells that controls the molecular flow between layer cellsCLDN 18 has two shear variants, CLDN 18.1 and CLDN 18.2The two are highly homogenous and have only eight sequence differences in amino acidsCLDN 18.2 protein is a CD20-like differentiation protein that is highly expressed in a variety of tumor tissues, such as stomach cancer (60-80%), pancreatic cancer (50%), esophageal cancer (30-50%) and lung cancer (40-60%), but is almost non-expressive in normal tissuesIn contrast, CLDN 18.1 is selectively expressed in cells of normal lungsTherefore, specific inhibition of CLDN 18.2 is agreed to be an effective way to treat advanced or metastatic stomach cancerFigure 1Since the results of a clinical trial of its anti-CLDN 18.2 inset antibody zolbetuximab at ASCO's 2016 meeting, CLDN 18.2 has attracted widespread attention in the industry as a brand-new anti-cancer molecular target, leading directly to the acquisition of $1.6 billion by Astellas that yearGastric cancer ranks third in global cancer deaths, is a refractive tumor, and has fewer targeted drugs and poor efficacyThe 5-year survival rate of gastric cancer is only about 5% to 20%, and the median total survival (OS) of patients with advanced gastric cancer is about 10 monthsFigure 2DrZhu Guidong reported on the discovery process and molecular characteristics of SPARx Pharmaceuticals' anti-CLDN 18.2 monoclonal antibody candidate SPX-101 in Abstract 3361Using mouse hybrid tumor technology, they obtained a series of highly active, highly selective anti-CLDN 18.2 rat-source antibodies through a variety of immune methodsThen, by sequence comparison and humanization, the humanized anti-CLDN 18.2 pilot antibody is obtainedIn order to further optimize the candidate antibodies, Sparx also matured the pilot antibodies through phage display screening technology, and obtained its candidate anti-CLDN 18.2 candidate antibody SPX-101 through comprehensive pharmacology, pharmacology, action, and safety evaluationHead-to-head experiments showed that SPX-101 had more than 100 times more affinity for CLDN 18.2 than zolbetuximab (0.013nM vs 1.54 nM, Figure C), and more than 4000 times more selective than CLDN 18.1 free protein or cell surface protein (Figure A/B) I124 isotope marker stakes showed a positive correlation between SPX-101's intake of 803 cells of stomach cancer and the expression level of CLDN18.2 In addition, SPX-101 has the advantages of binding force to acid, temperature insensitivity, and cell functional experiments, animal tumor models have shown better than Theay's similar drug zolbetuximab activity, showing the best potential of the same kind Figure 3 is the result of a portion of the SPX-101 animal experiment Isotope marker sision experiments showed that I124-SPX-101 was effective in the concentration of gastric cancer tissue that stablely expressed CLDN 18.2, but did not observe the same phenomenon in wild type 803 gastric cancer or isotope-labeled immunoglobulin G that did not express CLDN 18.2 (right) SPX-101 was also ideal in mice and rats with a longer half-life, but also lower levels of anti-drug antibodies (ADA), and lower immunogenicity predicted safety (top left) The mouse vaccination model showed that SPX-101 performed well in tumor inhibition in at least two tumor models (p.0018), and that head-to-head was more effective than Astely's zolbetuximab (left) figure 4 Abstract 534 describes the design, screening and evaluation process of SPARx Pharmaceuticals' anti-CLDN 18.2/PD-L1 dual-specific antibody candidate SPX-301 CLDN 18.2 is mainly expressed in stomach cancer, and PD-1 drug in gastric cancer effect and chemotherapy ratio is weak, so with CLDN 18.2 excellent selective selection of gastric cancer to increase PD-1 drug activity and response population is an ideal development strategy The SPX-301 is constructed using the SMARTOPTM model of Sparx's own intellectual property rights and is optimized by its LEMMAbTM phage display technology In addition to the advantages of high expression, no mismatch, high water solubility and high stability, this new dual-resistance build mode also emphasizes the optimization of acid resistance and low dissocing rate SPX-301 binds to CLDN 18.2, PD-L1 binding force, immunogenicity, and polymerization are similar to monoto-resistance, but the functional activity of sauor is shown in cell experiments that is superior to monogenic (figure below) Figure 5 animal experiments show that SPX-301 has a similar pharmacodynamic characteristics to monoclonal antibodies (bottom left) and the level of anti-drug antibodies (ADA) in mice is also very low, so it may be low immunogenicity and good safety (bottom) The mice inoculation experiments showed that SPX-301 was effective in inhibiting the growth of MC38 tumors with stable expression OF CLDN 18.2, and was statistically significant (p.01) According to Dr Zhu Guidong, the person reported lying pointed out that Sparx has started the sPX-301 pilot and safety evaluation, the establishment of SPX-301 stable cell line, and the yield and monoclonal antibodies are similar According to public database information, SPX-301 is the first time in the world to disclose the anti-CLDN 18.2/PD-L1 double-specific antibody Dr Dr Zhu Guidong also revealed that in order to accurately screen in-group patients and improve the success rate of clinical trials, Sparx has also developed an immunohistized companion detection kit (CDx) SPX-102 for CLDN 18.2 Using the CDx, they tested 456 Asian stomach cancer samples and found that 43% of gastric cancer samples were CLDN 18.2 positive The tissue slicing analysis of 328 patients with stomach cancer showed that the positive level of SPX-102 was negatively correlated with the patient's prognosis, so the SPX-102 accompanying test kit was expected to become an effective means to predict the prognosis of gastric cancer patients note : The original text has a limitation.